A hypothesis to explain the pattern of cytokine production observed in cultures of peripheral blood leukocytes from individuals who had been infected with multiple helminths, specifically spontaneous production of IL-10 in the absence of exogenous antigen (i.e. in unstimulated cultures); and the presence of a Th2 recall response, but not an IL-10 recall response, to A. lumbricoides antigens. (1) Multiple helminth infections could lead to stimulation of the immune system by hundreds of different antigens, including antigens that are cross-reactive with self antigens. (2) Strong helminth-specific and nonspecific polyclonal Th2 immune responses, with the differentiation and expansion of memory cells, would result from such infections. The Th2 immune response could lead to helminth-specific and non-specific polyclonal IgE production, to eosinophil expansion and activation, and to inflammation. The high levels of polyclonal IgE could theoretically inhibit mast cell activation, by competition with allergen-specific IgE for FcϵRI receptors on mast cells, causing inhibition of immediate hypersensitivity skin test to allergens). (3) A consequent differentiation and expansion of helminth-specific Tregs, some of them cross-reactive with self antigens (and some perhaps only autoantigen-reactive, as a consequence of tissue damage by inflammation) could occur (for the sake of clarity, only cross-reactive and helminth-specific Tregs are shown). (4) The cross-reactive/self antigen-specific Tregs would be maintained in a steady state of activation by self antigens, and would release low levels of regulatory cytokines, including IL-10. The spontaneous production of elevated levels of IL-10 could suppress mast-cell degranulation. Because these Tregs could be maintained through continuous stimulation to self antigens in vivo, they would not be further stimulated by helminth antigens in vitro. TLR- toll-like receptor.